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CELLULAR MECHANISMS CONTROLLING THE MOSAIC OF SURVIVNG CONES IN RETINITIS PIGMENTOSA RETINAS
By Yerina Ji
A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY NEUROSCIENCE
Copyright 2013 Yerina Ji

In this research project, there are four main parts. Scientists have for long tried to understand the fate of cones in RP retinas in determination to rescue them from degeneration at later stages of the disease following rod degeneration. However, no past studies have examined cone mosaic in depth in the whole mount of RP retinas. In the first part, the extensive remodeling of cone mosaic in the S334ter-line-3 rat retinas was examined in depth. We have found that cones in these RP retinas rearranged themselves in a regular array of rings and survived for a long time after rod deaths. The rings continued to remodel through later stage of life as their mean size and quantity increased with the progression of disease before the eventual cone deaths. Similar photoreceptor distribution pattern of rings are also observed in human patients with some eye diseases, and this makes the current study even more significant (Carroll et al., 2004; Choi et al., 2006; Duncan et al., 2007; Joeres et al., 2008; Rossi et al., 2011). In the second part of the research project, we examined our hypothesis that rod deaths would have some relationship to the cone rings. We have found that rods degenerated initially in random scatter. Gradually, these dying rods seemed to affect the neighboring rods as they led to clusters of deaths, which then radially propagated outward in a circular wave fashion to create growing rings of dying rods leaving growing holes in their mosaic. These holes were always accompanied by cone rings that occurred exactly at the same locations. Thus, we have shown that rod deaths triggered the remodeling of cone mosaic as they migrated away from regions where rods were unhealthy or dead. It was previously reported that Müller cells aided the migration of neurons (Sullivan et al., 2003). In the third part of the study, we showed that cones and Müller cells in our RP retinas were indeed in close association. Moreover, we found that Müller cells remodeled remarkably in their apical processes to fill inside each cone ring. We then aimed to examine whether or not the Müller cells were necessary for cone rings. We performed the experiment this by poisoning the Müller cells and showed ring deformation. In conclusion, we have illustrated that proper metabolism of Müller cells and their interaction with cones were necessary for the maintenance of cone rings. In the final part of the study, a broader and more fundamental question of what determines and modulates the regularity of the cone mosaics in normal and in RP rat retinas was addressed. For this investigation, tissue inhibitor of metalloproteinase (TIMP-1) known to modulate the degradation and turnover of the extracellular matrix, and also affect the ability of photoreceptors to migrate, was administered into the eyes of both normal and RP rats. The results indicated that TIMP-1 led to striking change in the cone mosaic in both normal and in RP retinas. Upon TIMP-1 application, cones in normal retinas showed tendency to clump while cones in RP retinas lost their ring arrangement and regained homogeneity of their mosaic. Most important of all, the TIMP-1in normal and RP retinas disrupt the regularity of cone mosaics as they became close to that of random distribution. Therefore, we conclude that the cone-ECM interaction is necessary for controlling of regular cone spacing. In addition, we have shown that TIMP-1 is one of the key factors that take part in modulation of such process. We hope that the addition to knowledge harvested from the current research would eventually lead to better approach for therapy against Retinitis Pigmentosa and other above-mentioned eye diseases, where retinal transplantation or reengineering of cone mosaic is necessary.

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ii
CELLULAR MECHANISMS CONTROLLING THE MOSAIC OF SURVIVNG CONES IN RETINITIS PIGMENTOSA RETINAS
By Yerina Ji
A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY NEUROSCIENCE
Copyright 2013 Yerina Ji